The invention relates to medicine, namely to methods of endovascular drug therapy, and, in particular, to methods of locally increasing a concentration of drugs in the walls of arteries and veins, in particular for prevention of coronary restenosis.
A number of drugs require intravenous or intra-arterial infusion, by passing the digestive system, so as to preserve the drugs from degradation by catalytic enzymes in the digestive tract. Also, application of a drug with high toxicity in high concentration requires accurate control of their delivery. Moreover, a delivery agent, not being an active pharmacological agent, can still boost the activity of the delivered drug by mediation of its therapeutic activity.
At present, the role of a delivery agent is usually played by a stent with a drug coating. The active substance (paclitaxel, sirolimus, zotarolimus) is dissolved in the polymeric coating of the stent, and is then gradually released, preventing proliferation of smooth muscle cells of an arterial wall, thus preventing evolution and occurrence of restenosis of the stented arteries. At the same time, the drug eluting stents induce an inflammation and can even result in subsequent thrombosis owing to secondary hypersensitivity in some patients, and also owing to a slowdown of endothelization process (see N. Malik et al., “Phosphorylcholine-coated stents in porcine coronary arteries: in vivo assessment of biocompatibility,” J Invasive Cardiol. 13 (2001), pp. 193-201, A. V. Finn et al., “Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents,” Circulation 112 (2005), pp. 270-278, R. Virmani et al., “Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?” Circulation 109 (2004), pp. 701-705). The polymeric coating extends the stage of thrombogenesis and of acute inflammation. All existing intravascular stents used in a clinical practice, have paramagnetic properties, except for diamagnetic nitinol self-expandable stents.
There are alternate ideas of a drug delivery to a vascular wall, in particular, by using composite super-paramagnetic nanoparticles, the ferromagnetic or paramagnetic stents and an exterior magnetic field. At the same time, some data are available about negative biological effects on humans of the impact of a permanent magnetic field with the intensity over 1 Tesla (see Y. Kinouchi, “Electromagnetic Mechanisms of Biomagnetic Effects,” The Journal of the Japanese Society of Magnetic Applications in Dentistry, (1997) Vol. 6, No. 1, pp. 13-17). Several comprehensive reviews have attempted to postulate human exposure limits and recommends a level of 0.02 T for continuous exposure. The apparent basis for the 0.02 T recommendation derives from the fact that lowest exposure level which no effect was reported was 0.008-0.01 T (see E. E. Ketchen et al., “The Biological Effects of Magnetic Fields on Man,” Am. Ind. Hyg. Assoc. J., 39:1-11 (1978) and Z. N. Nakhilnitskaya, “Biological Effects of Permanent Magnetic Fields,” Space Biology and Aerospace Medicine, 8(6): 1-25 (1974)). Two general types of effects from exposures to magnetic fields are postulated as a result of theoretical calculations: magnetomechanical and electromagnetic. Magnetomechanical forces could produce translation and rotation of particles (molecules, cells, etc.), and electromagnetic forces could produce induced voltages and flow modification.
A magnet-controlled system of the targeted drug delivery to destination places, associated with magneto-sensitive particles (see U.S. Patent Publication No. 2006/0041182), where an intravascular magnetized device (for example, a stent made of a paramagnetic material) is implanted, in advance, by a catheter, in the area of interest of the blood vessel, then a polymeric magneto-sensitive carrying agent prepared in the form of particles containing a drug, is injected into the blood vessel, and thereafter, a magnetic field from an exterior source is activated, whereby a gradient magnetic field is generated in the area of interest of the blood vessel, attracting particles of the magneto-sensitive carrying agent.
However, this method cannot be used in organs and vessels with an intensive blood flow. In particular, the aorta and coronary arteries of heart have such high parameters of volumetric velocity of a blood flow, that particles of the carrying agent with size range 0.01 to 1.0 microns will only concentrate in the field of interest in case of the magnetic field induction in excess of 1.0 Tesla. This is unpredictable for the cardiac electrophysiology, for functioning of pace-makers of heart rhythm and carries a risk generating life-threatening arrhythmias. Also, the unpredictable Theological effects caused by concentration of erythrocytes are possible in the area in question. For the particles containing drug with size range 2 to 10 microns, i.e., comparable to size of the blood cell components, concentration on magnetosensitive implants under the force of an exterior magnetic field can result in magneto-induced thrombogenesis. Also, a strong exterior permanent magnetic field has an impact on the central nervous system.
A conventional method of use of a ring catheter (see U.S. Pat. Nos. 5,951,566 and 5,851,218), intended for slow expansion of walls at vasoconstriction without blocking a fluid stream and/or the drainage of sediments on the walls of blood vessels, is known. The method consists of an introduction of a catheter with a conductor of a magnetic field and an inductance coil, and delivery to the area of interest, along with the catheter, of a stent coated with activatable adhesives and provided with elements containing permanent magnets. Interacting of magnetic fields of the inductance coil and of the permanent magnets allows to expand the stent and to intensify the process of implantation of adhesive specimens in the walls of the blood vessel. However, in such an arrangement, the magnetized micro-carrying agents will be attracted to an element with the maximum magnetic intensity, i.e., to the catheter and its components (to the coil core and/or to the ring permanent magnet), instead of the stent on walls of the blood vessel. Thus, it will not be possible to use these micro-carrying agents for intensification of treating the walls of the blood vessel with the drugs. This known method is inapplicable to processing intravascular areas with magneto-sensitive carrying agents containing a drug.